Essential hypertension in African Americans is both more prevalent and more severe than it is in the Caucasian population. In general, hypertensive African Americans are at greater risk for heart attacks, strokes, and kidney failures than their counterparts from other ethnic backgrounds. Decades of clinical observations and physiological studies have implicated sodium handling in the African American kidney as a potential contributor to the etiology of hypertension in this population. The epithelial sodium channel (ENaC) plays a crucial role in sodium reabsorption and excretion in the distal nephron and collecting duct. It is therefore an important control point in the regulation of long term arterial blood pressure. Recently, mutations in ENaC were shown to cause Liddle's syndrome, a rare form of hypertension, demonstrating that altered ENaC function can directly affect blood pressure. The central hypothesis of this proposal is that ENaC also contributes to the more commonly seen form of the disorder, essential hypertension, in African Americans. We show preliminary evidence for suggestive linkage of polymorphic markers at loci for ENaC to the trait of essential hypertension in African American sib-pairs. We have identified ten novel variants in the alpha and beta subunits of ENaC. Of these, seven are seen only in populations with African origins, and one in both African and Caucasian populations. Three of these variants, beta-T594M, alpha-A663T and alpha-C618F are more prevalent in hypertensive than normotensive populations in a statistically significant manner. We will analyze the effect of these variants in three different expression systems: oocytes, lymphocytes and mammalian cells. Detailed electrophysiological analysis of one of these variants has been initiated and preliminary evidence for its ability for enhanced sodium conductance demonstrated. We propose to expand this combination of genetic and physiological analyses to all the ENaC variants in AA populations. In the short term, these studies may reveal new information on the regulation of EnaC. Over the longer term, they may provide a molecular basis for some portion of the phenotype of essential hypertension in African Americans.